JP2000007999A - Stabilized monomer adhesive composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an adhesive composition with a longer and improved storage life without sacrifice of performances as the adhesive in both industrial and medical uses. SOLUTION: The objective composition comprises a polymerizable 1,1- disubstituted ethylene monomer in a liquid state and in a gaseous state, at least one gaseous anionic stabilizer and at least one liquid anionic stabilizer, wherein the at least one liquid anionic stabilizer is an extremely strong acid or the at least one liquid anionic stabilizer is a strong acid and the at least one gaseous anionic stabilizer comprises at least one compound selected from the group consisting of boron trifluoride and hydrogen fluoride.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to monomeric and polymeric adhesive compositions and to a process for preparing these compositions for industrial and medical applications.

[0002]

BACKGROUND OF THE INVENTION Monomer and polymer adhesive compositions are used in both industrial (including household) and medical applications. These adhesives include α-
Includes 1,1-disubstituted ethylene monomers and polymers such as cyanoacrylates. Since the discovery of the adhesion properties of such monomers and polymers, cure rates, these monomers and polymers have found wide application due to the resulting bond strength and their relatively easy use. With these features, α
-Cyanoacrylate adhesives have become the primary choice for large applications such as adhesive plastics, rubber, glass, metal, wood and more recently biological tissues.

[0003]

An adhesive having a high curing rate and a high bond strength can be obtained through a process for optimizing the industrial production of a 1,1-1-disubstituted ethylene adhesive composition. It became so. However, the desire to provide an adhesive with a fast cure rate and high bond strength has led to problems with shelf life. The shelf life of these adhesives is primarily related to stability (ie, homeostatic properties of the composition), uncured physical properties, cure rate of the adhesive, and physical properties of the composition during final cure. . For example, the shelf life of an α-cyanoacrylate monomer composition is related to the amount of time that the composition can be stored before polymerization occurs at unacceptable levels. This unacceptable level is indicated by the level of polymerization product that diminishes its usefulness for the application for which the composition was manufactured.

The monomeric form of α-cyanoacrylate is known to be very reactive and to rapidly polymerize in the presence of even small amounts of initiator, including in the air or on the wet surfaces of animal cells. I have. The α-cyanoacrylate monomer can be anionically polymerizable, radically polymerizable or polymerizable by zwitterions or ion pairs, thereby forming a polymer. Once polymerization begins, the cure rate can be very fast. Therefore, in order to obtain an α-cyanoacrylate monomer composition having a long storage life, a polymerization inhibitor such as an anionic stabilizer and a radical stabilizer is often added to the composition. However, the addition of such a stabilizer may significantly slow down the curing speed of the composition, and therefore, when the α-cyanoacrylate adhesive is manufactured industrially, the added stabilizer may be used. The amount of the agent is minimized so as not to adversely affect the curing speed.

[0005] One of the anionic stabilizers that has been used is sulfur dioxide. Unfortunately, this stabilizer provides a stabilizing effect, but reduces the cure rate as the composition ages. This is because sulfur dioxide is continuously oxidized to sulfuric acid, which is also an anionic stabilizer. As the concentration of sulfuric acid in the composition increases, the cure rate of the composition decreases. This effect, often referred to as "slowdown", is a serious problem that arises in the manufacture and storage of α-cyanoacrylate adhesives industrially. In extreme cases, the level of sulfuric acid may be too high to cure the monomer composition. Furthermore, the conversion of sulfur dioxide to sulfuric acid reduces the amount of sulfur dioxide in the gas phase, which ultimately results in the formation of polymers in the headspace (gas phase) of the vessel. Such polymerization in the container will further reduce the shelf life of the composition.

In addition to using these adhesives industrially, 1,1-disubstituted ethylene adhesives have also been used for medical purposes. These applications include surgical sutures and staples as replacements or aids for closing wounds, and surface wounds such as lacerations, abrasions, burns, stomatitis, inflammation and other open surface wounds. It is used to protect coatings. Preferably, the cyanoacrylate adhesive used in medical applications has a shelf life of at least 2 months. To obtain a useful shelf life, anionic and radical stabilizers have been added to the monomer composition.

For example, Banitt et al US Pat. Nos. 3,559,652 and Leung et al.
U.S. Pat. As disclosed in US Pat. No. 5,582,834, suitable stabilizers for alpha-cyanoacrylate compositions used in medicine include Lewis acids such as sulfur dioxide, nitric oxide and boron trifluoride and hydroquinone, monomethyl ether. There are radical stabilizers such as hydroquinone, nitrohydroquinone, catechol and monoethyl ether hydroquinone. It is also known to combine sulfur dioxide and sulfonic acids, which are anionic stabilizers, for example in British Patent Application GB2
107328A. However, the use of such two stabilizers in combination does not solve the problem of "speed reduction" found in the 1,1-disubstituted ethylene adhesive composition.

In addition to extending shelf life, cyanoacrylate compositions used in medical applications must be sterile. Since it is important to keep these compositions sterile and maintain their state, when additives such as anionic fungicides or radical fungicides are added to the α-cyanoacrylate composition, they should be added before sterilization. It is. However, regardless of the type and number of additives, α-
It can often be difficult to sterilize the cyanoacrylate adhesive composition. For example, widely used sterilization methods, such as heat sterilization and ion radiation, are often not suitable for use with cyanoacrylate monomer compositions. Even when stabilizers are present, problems arise because of the monomer polymerization during the sterilization process. In many cases, the polymerization caused by the disinfection may be too advanced and the resulting product may be unusable. Further, even if the sterilized product is still usable, the shelf life at room temperature may be reduced to a point where the product is unsuitable for commercialization.

The methods currently used for packing and disinfecting α-cyanoacrylate adhesive compositions require that the packing and disinfection steps be performed quickly and continuously in order to increase efficacy and productivity. It has been developed under the recognition of However, these methods have not been able to achieve the desired shelf life of the adhesive composition in all packing materials.

Furthermore, during the disinfection process, many or all disinfectants may be consumed or converted to other compounds. McDonnel et al., U.S. Pat.
No. 5,530,037 discloses that if low levels of sulfur dioxide are used to sterilize cyanoacrylate, all sulfur dioxide is converted to sulfuric acid during the sterilization process. Although the use of low levels of sulfur dioxide can minimize polymerization during the pasteurization process and extend the shelf life of the pasteurized α-cyanoacrylate adhesive composition, It may be possible to increase the shelf life by having an increased amount of sulfur dioxide present. Unfortunately, however, initially high levels of stabilizers can impair the general properties of the adhesive, resulting in a shorter shelf life than desired.

[0011] The patent to McDonnell et al. Interestingly mentions that the radical stabilizers butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BH) are combined with 100 ppm (final concentration) of sulfur dioxide.
T), these are substantially 1000 p
It is disclosed that if it is not present at concentrations above pm, it will not be effective in stabilizing the α-cyanoacrylate adhesive composition when sterilized by gamma radiation (McDo).
(See Example 4 of the patent of Nnell et al.). Accordingly, there is a need for improved α-cyanoacrylate adhesive monomer compositions that have a longer shelf life without sacrificing adhesive performance in both industrial and medical applications.

[0012]

SUMMARY OF THE INVENTION It is an object of the present invention to provide an improved adhesive composition, a method for producing the adhesive composition, and a method for sterilizing the adhesive composition. This improved composition is obtained by a novel combination of stabilizers.

The present invention comprises a polymerizable α-cyanoacrylate monomer, at least one stabilizer which stabilizes the vapor state (also referred to herein as a “gas phase anionic stabilizer”), Provided is a monomer-containing adhesive composition comprising at least one additional stabilizing agent that stabilizes a state (also referred to herein as a "liquid phase").
As used herein, a stabilizer is a polymerizable 1,1-
It refers to a substance that blocks or prevents the initiation of polymerization of a disubstituted ethylene monomer or reduces the overall polymerization rate of a composition containing a polymerizable 1,1-disubstituted ethylene monomer. In the polymerization, the initiation or chain extension is prevented. In embodiments, the liquid phase stabilizer is a strong acid, with very strong acids being preferred.

According to the present invention, by combining the polymerizable monomer with at least one gas phase stabilizer and at least one liquid phase stabilizer, a similar one lacking either or both of these stabilizers can be obtained. A monomer adhesive composition having an improved / extended storage life as compared with the α-cyanoacrylate monomer composition of (1) is obtained. It is known to add a polymerization inhibitor (stabilizer) to a monomer adhesive composition, but as in the present invention a single monomer adhesive composition, at least one vapor stabilizer and at least one liquid Combinations with phase stabilizers have not been previously recognized. Because of the low molecular weight of α-cyanoacrylate monomers, some of the monomers are in the vapor phase. This is especially true in sterilization processes where heat is applied or generated. The reason is that heat increases the amount of monomer in the vapor phase. Unstable monomers in the vapor phase polymerize, for example, on the vessel wall. Therefore, it is necessary to stabilize the vapor and liquid phases in order to minimize the undesired polymerization of monomers and to improve shelf life.

The present invention also includes a method for producing such a stabilized composition. The method for producing the stabilized composition includes a step of combining the monomer and the stabilizer, and may further include a step of packing and sterilizing the monomer-containing adhesive composition. The compositions prepared and packed according to the present invention have a longer shelf life and therefore a greater utility compared to prior art α-cyanoacrylate monomer adhesive compositions.

The present invention further includes a method of sterilizing a monomer-containing adhesive composition that includes at least one gas phase stabilizer and at least one liquid phase stabilizer. The monomeric composition can be sterilized without causing unacceptable levels of polymerization. Accordingly, the present invention also provides a germicidal monomer-containing adhesive composition having a longer shelf life and a higher ratio of monomer to polymer than compositions prepared by conventional methods.

[0017]

DETAILED DESCRIPTION OF THE INVENTION In the present invention, a stable monomeric adhesive composition is prepared by adding at least one gas phase stabilizer and at least one liquid phase stabilizer to a composition comprising a monomer adhesive. Manufacturing things. By combining at least one gas phase stabilizer and at least one liquid phase stabilizer in accordance with the present invention, the monomers of the composition are prevented from polymerizing to a greater extent than achieved with prior art compositions. .

The anionic gas phase stabilizer can be selected from known stabilizers including, but not limited to, sulfur dioxide, boron trifluoride and hydrogen fluoride.
The amount of the anionic gas phase stabilizer added to the monomer composition depends on the liquid phase stabilizer selected in combination therewith, the monomer to be stabilized and the packing material used for the composition particles. In order to stabilize the monomer present in the gas phase even after the sterilization step is completed, an anionic gas phase stabilizer is added in an amount sufficient to leave at least some anionic gas phase stabilizer in the gas phase. Preferably, 200 ppm
It is preferable to add each of the anionic gas phase stabilizers so that the concentration of the anionic gas phase stabilizer is adjusted to a concentration of 1%. In a preferred embodiment, each anionic gas phase stabilizer is present in an amount of about 1 to 200 ppm, more preferably about 10 to 75 ppm, and even more preferably about 10 to 50 ppm.
ppm, most preferably about 10 to 20 ppm. Using known techniques without undue experimentation, one skilled in the art would be able to determine the amount used.

In an embodiment, the gas phase contains, in particular, anionic stabilizers of sulfur dioxide. Other embodiments include, inter alia, boron sanfluoride or hydrogen fluoride stabilizers. In some embodiments, a combination of sulfur dioxide and boron trifluoride or hydrogen fluoride is preferred.

In some embodiments, the liquid phase anionic stabilizer is a very strong acid. As used herein, refers to an acid is an aqueous pK _a is the very strong acid is less than 1.0. Suitable very strong acidic stabilizers include, but are not limited to, very strong mineral and / or oxygenated acids. Such an extremely strong acid scent is not intended to be limited, but sulfuric acid (pK _a -3.0), perchloric acid (pK _a -5.0), hydrochloric acid (pK _a -7.0) , hydrobromic acid (pK _a -9.0), fluorinated sulfonic acid (pK _a <-1
0.0) and chlorosulfonic acid (pK _a -10.0). As an example, a very strong acidic liquid phase anionic stabilizer is added to a final concentration of 1-200 ppm. Preferably, a very strong acidic liquid phase anionic stabilizer is present at a concentration of about 5 to 80 ppm, more preferably about 10 to 40 ppm. Those skilled in the art will be able to determine the amount of very strong acidic liquid phase anionic stabilizer to use without undue experimentation using known techniques.

Preferably, the very strong acidic liquid phase anionic stabilizer is sulfuric acid, perchloric acid or chlorosulfonic acid. More preferably, the very strong acidic liquid phase anionic stabilizer is sulfuric acid.

In the examples, sulfur dioxide is used as a gas phase anionic stabilizer and sulfuric acid is used as a liquid phase anionic stabilizer.

In a preferred embodiment, boron trifluoride and / or hydrogen fluoride can be used in combination with a very strong acidic stabilizer. Such a combination is particularly beneficial with regard to plastic containers and is applicable to all monomer adhesive compositions of the present invention, but is particularly useful for monomer adhesive compositions for industrial applications. Fit. Since boron trifluoride and hydrogen fluoride are also oxidized and do not become liquid phase anionic stabilizers, boron trifluoride and / or
Alternatively, "speed loss" of the composition can be avoided by using hydrogen fluoride. Therefore, by using these gas-phase anionic stabilizers, a composition having a particularly prolonged storage life can be obtained.

In a preferred embodiment, boron trifluoride and / or hydrogen fluoride are used in combination with sulfur dioxide and an anionic stabilizer of a very strong acid. For example, a combination of boron oxyfluoride, sulfur dioxide and sulfuric acid can be used. This combination contains small amounts of boron trifluoride or hydrogen fluoride in connection with sulfur dioxide and an anionic stabilizer of very strong acids. Also,
This combination can also be used with many monomer adhesive compositions and packing materials. Boron trifluoride and / or hydrogen fluoride may serve to remove destabilizing substances present on the surface of the packing material, thereby shortening the shelf life of the packing composition. The polymerization initiator can be removed. The amount of boron trifluoride and / or hydrogen fluoride used should be selected to increase shelf life without unacceptably damaging the container. Such amounts will depend on how the compositions and containers are selected and their volume, but will be determined without undue experimentation by one of ordinary skill in the art.

In this embodiment, the liquid phase anionic stabilizer is strongly acidic. The strong acid used here is an acid having a water-soluble pKa of 2 or less. Therefore, strong acids include the very strong acids described above.

The strong acid is preferably a strong inorganic acid or a strong organic acid, but is not limited thereto. Examples of such an acid include, but are not limited to, sulfonic acids such as methanesulfonic acid. In this example, the liquid phase strong acid stabilizer had a final concentration of 2
It is added so as to be not more than 00 ppm, preferably 5 to 80 ppm, more preferably 10 to 40 ppm. The strong acid liquid phase anionic stabilizer in this example is an organic sulfonic acid.

The composition may optionally contain at least one other anionic stabilizer to prevent polymerization. Here, these other stabilizers will be referred to as secondary anionic stabilizers in contrast to the strong acids or extremely strong acidic liquid phase anionic stabilizers. On the other hand, the above-mentioned strong acid or extremely strong acidic liquid phase anionic stabilizer is referred to as a primary anionic stabilizer. A secondary anionic stabilizer can also be included in the adhesive composition, for example, to control the rate of crosslinking of the composition.

The secondary anionic stabilizer usually has _a higher pKa than the primary anionic stabilizer. And, like the molecular weight of the crosslinked adhesive, it can also be used to more precisely control the crosslinking speed and stability of the adhesive. Any mixture of primary and secondary anionic stabilizers can be used so long as the chemical properties of the composition do not depart from the desired properties and do not interfere with the desired polymerization of the composition. Further, in medical applications,
The mixture should not exceed the toxicological tolerance.

As the above-mentioned secondary anionic stabilizer, 2
Those having _a water-soluble pKa ionic constant in the range of from 8 to 8 are preferable, and those having an ionic constant in the range of from 2 to 6 are more preferable. Those having a certain ionic constant are preferred. As the secondary anionic stabilizer, phosphoric acid (pK _a = 2.
2), acetic acid (pK _a = 4.8), benzoic acid (pK _a =
Preferred are, but not limited to, organic acids such as 4.2), chloroacetic acid (pK _a = 2.9), cyanoacetic acid and mixtures thereof. Among them, organic acids such as acetic acid and benzoic acid are particularly preferable as these secondary anionic stabilizers. The amount of acetic acid and / or benzoic acid in this example is 25 to 500 ppm. A typical concentration of acetic acid is 50-400 ppm, preferably 75-300 ppm.
pm, and more preferably 100 to 200 ppm. When a relatively strong acid such as phosphoric acid is used, the concentration of the acid is 20 to 100 ppm, preferably 30 to 30 ppm.
-80 ppm, more preferably 40-60 pp
m.

In this example using only an anionic liquid phase stabilizer as a strong acid liquid phase anionic stabilizer, the composition was prepared using either gaseous boron trifluoride or hydrogen fluoride as a gas phase anionic stabilizer. Preferably, one or both of them are contained. In these examples, "speed loss" can be prevented by using boron trifluoride and / or hydrogen fluoride in addition to the strong acid liquid phase anionic stabilizer described above.
This can improve the shelf life of the composition (compared to the case where sulfur dioxide is used as a gas-phase anionic stabilizer). Since neither boron trifluoride nor hydrogen fluoride is oxidized throughout the time of addition to the liquid phase stabilizer, the increase in time required for the adhesive composition in monomeric state to polymerize is due to the Substantially not found in the production process. In embodiments where boron trifluoride and / or hydrogen fluoride is used only as a gas phase stabilizer, it is preferred that the container is not made of glass. However, in some embodiments, very small amounts of gas-phase anionic stabilizers are used without significantly affecting the condition of the glass container.

It is also possible to use a mixture of at least one gas phase stabilizer and at least one liquid phase anionic stabilizer. For example, a mixture of sulfur dioxide and sulfuric acid, a mixture of sulfur dioxide and perchloric acid, a mixture of sulfur dioxide and chlorosulfonic acid, a mixture of boron trifluoride and sulfuric acid,
A mixture of sulfur trifluoride and perchloric acid, a mixture of boron trifluoride and chlorosulfonic acid, a mixture of boron trifluoride and methanesulfonic acid, a mixture of hydrogen fluoride and sulfuric acid, a mixture of hydrogen fluoride and hydrogen peroxide A mixture of chloric acid, a mixture of hydrogen fluoride and sulfuric acid, or a mixture of hydrogen fluoride and methanesulfonic acid can be used. Further, a mixture of boron trifluoride, sulfur dioxide, and sulfuric acid can be used. In addition to being compatible with the equipment used to manufacture and pack the packing materials and compositions, the selected adhesive compositions and the two
A variety of anionic stabilizers are selected. In other words,
After packing, the gas phase stabilizer, liquid phase stabilizer, and monomer should be selected to form a mixture such that a stable and substantially non-polymerized adhesive composition is obtained.

The present invention relates to an adhesive composition containing at least one free-radical stabilizer, which is also known as a free-radical terminator or antioxidant. It is to provide an adhesive composition comprising at least one gas-phase anionic stabilizer and at least one anionic stabilizer. It is well known to add free radical stabilizers to α-cyanoacrylate compositions, but at least one gas phase anionic stabilizer and at least one liquid phase anionic stabilizer. The advantages obtained by adding a mixture with free radical stabilizers have not been recognized in the past. Since the composition of the present invention has the above-described embodiment, the shelf life is improved. In addition, by adding at least one gas phase anionic stabilizer and at least one liquid phase anionic stabilizer to the composition comprising the stabilizer, a stable and sterile with improved shelf life. Is sterilized so as to obtain the composition of

[0033] The compositions of the present invention also include an agent. Compositions with drugs are often preferred for pharmaceutical use. The drug is added to the monomer-containing adhesive composition prior to filling or applied to the tissue prior to application to the monomer-containing adhesive composition. The drug has a function of initiating and / or accelerating the polymerization of the monomer composition in addition to the function as the drug.

Drugs include antibiotics, antibacterials, preservatives, bacteriocins, spermatozoa, antiinfectives, steroids, anesthetics, bactericides, antiinflammatory agents, antibacterial agents, antiviral agents, antitumor agents, growth agents Accelerators, these compounds, and the like can be exemplified, but are not limited thereto. Representative agents include quaternary ammonium halides such as benzalkonium chloride and benzethonium chloride, and chlorohexane sulfate (chlorhexi).
dine sulfate, gentamicin sulfate, hydrogen peroxide, quinolone, thiourea, silver acetate, silver benzoate, silver carbonate, silver chloride, silver citrate, silver iodide, and silver sulfate, but are not limited thereto. ), Sodium hypochlorite, and salts of sulfasalazine, including but not limited to salts of silver, sodium, and zinc, and mixtures thereof. However, the present invention is not limited to these. Preferred agents are those that promote the generation of anionic or radical radicals,
Further, there are an ion pair, a radical, and the like.

In the examples, alkali benzyldimethylammonium chloride having an alkyl containing 6 to 18 carbon atoms (benzalkonium chloride: BA
C) a quaternary ammonium halide such as its pure compound, or a mixture thereof, or silver, sodium,
Sulfarazine salts such as zinc salts and the like are preferred as drugs.

The drug can exert a pharmacological effect where it is applied (ie, in the tissue to which the drug is applied). Alternatively, a systematic effect (systemic means not only the whole body of the patient but also a part other than the place where the drug is applied) can be exerted. In embodiments where the drug is used in an amount sufficient to exert a pharmacological effect, the drug is absorbed, transported,
Alternatively, it is distributed to the location of the patient where pharmacological activity is desired, such as the heart or lymphatic system. Drugs can be in the form of a solid, such as a powder or a solid film,
It exists in a liquid state such as a paste. In addition, additives such as a surfactant, an emulsifier, and a vehicle can be added to the drug.

In another embodiment, the present invention relates to a method for treating a skin, including (but not limited to) a superficial tear, burn, or abrasion, or a mucosal wound, including but not limited to a superficial or topical wound. It also includes methods for dealing with typical pathology. The method involves the preparation of an adhesive composition containing the drug and applying the composition to the area to be treated. Alternatively, (a) applying a drug (a polymerization initiator or a polymerization accelerator) to a tissue portion;
(B) applying a polymerizable monomer-containing adhesive composition to the drug; (c) polymerizing the composition;
(D) applying the composition at least once to the same location as appropriate.

The film thickness suitable for topical application is preferably from 1 to 10,000 μm, for example from 1 to 1000 μm. In an embodiment, the film is formed to have a film strength of at least 5 mmHg, preferably 5 to 400 mmHg, more preferably 50 to 400 mmHg.

In one embodiment, the invention provides a method for delivering a drug to a tissue. The method comprises producing a composition containing the drug, applying the composition to a location, polymerizing the composition, and transporting the drug to a location of interest for a time sufficient for the drug. Holding the polymerized composition in contact with the location. Or (a) applying a drug (a polymerization initiator and / or a polymerization accelerator) to a location (for example, directly to a tissue); (b) applying a monomer-containing composition to be polymerized to the drug; (C) optionally, the composition comprises at least one
The times include applying to the location. The thickness and strength of the film are preferably as described above.

[0040] In an embodiment, the drug is at a constant rate throughout the time in contact with the affected tissue,
Alternatively, it is administered to the tissue at a near constant rate. The present invention also provides a kit for providing the composition of the present invention to a user. In this embodiment, the invention provides a kit for delivering a drug to a patient. In this example,
The kit includes a container having a polymerizable monomer composition such as a cyanoacrylate adhesive. The kit also includes another container having a medicament. Alternatively, the kit may comprise a single container holding a composition having both an adhesive and a drug. In an embodiment, the kit comprises a number of containers. Each container holds one or more polymerizable monomers and one or more drugs. Some of the containers may also hold a mixture of adhesive and drug.

When the commonly packaged polymerizable monomer composition is bound, it initiates the polymerization of the monomer or improves (ie, accelerates) the rate of polymerization of the monomer to form a polymeric adhesive. The drug is selected to have a function. Drugs and compatible polymerizable monomers are readily determined by those skilled in the art.
The agent is supplied to the kit in an amount that exerts a pharmacological effect when applied topically (ie, directly to the tissue).

The compositions of the present invention can be manufactured and sterilized in very small quantities. Typically, sterilized α-
Cyanoacrylate compositions have high capacities (i.e., 1.
5 mL). When applied to medical applications, the above-mentioned large capacity is not preferable because much of the composition is discarded at the first use because impurities may be mixed into the composition at the first use. Therefore, it is preferable to provide sterilized α-cyanoacrylate in a small volume. According to the present invention, in combination with a free radical stabilizer,
The use of at least one gas-phase anionic stabilizer and at least one liquid-phase anionic stabilizer makes it possible to sterilize 1 mL or less of the adhesive synthetic agent. Accordingly, the sterilized composition of the present invention as described above is an improvement over currently used sterile compositions.

Preferably, the composition of the present invention is packaged such that the volume of the adhesive composition per packing (ie, container) is 1 mL or less. More preferably, packaging is performed so that the volume of the adhesive composition is 0.6 mL or less. The composition of the present invention is sterilized by any suitable means such as, but not limited to, dry heat sterilization, gamma irradiation, microwave irradiation, and electron beam irradiation.

In an embodiment, the adhesive composition of the present invention is sterilized. In embodiments where the composition is used for medical applications, the sterilized composition should have a low level of toxicity to active tissues throughout its useful life. According to the present invention, at least one gas phase and at least one liquid phase anionic stabilizer can sufficiently inhibit polymerization of the monomer (ie, polymerization of the composition). Also, sterilization can be achieved without reaching undesired levels of polymerization or without increasing the rate of crosslinking due to transient stabilization resulting from methods such as those disclosed in the prior art. For example, a sterilized composition according to an embodiment of the present invention increased in viscosity in the range of 300% or less as a result of sterilization. The viscosity level is determined by known methods. For example, a Brookfield cone-plate viscometer equipped with a spindle size CP-40 (Brook)
field Cone-Plate Viscomet
er) at room temperature (about 21-25 ° C.). This device uses a viscosity reference (Viscosite).
y Reference Standard) within the same range as the test sample. Each sample is measured three times and the average is recorded.

The monomer-containing composition is packaged in a suitable container formed from materials including, but not limited to, glass, plastic, metal packages, and film packages. Suitably, a container is used that separates the composition and does not undesirably damage or degrade the components of the container or monomer composition. When plastics are used at a dry heat sterilization temperature (typically, at least 160 ° C.), their stability is lost. Therefore, when such dry heat sterilization is used, glass is used. Is preferred. For example, but not limited to ampoules, vials, syringes, pipettes, etc.
Can be exemplified. In a preferred embodiment, it comprises a hermetically sealed container. The container may be of any size, but in the examples, a container having a total volume of 1 mL or less is used. For example,
A container having a total volume of 1 mL contains 0.6 mL of the monomer composition.

When sterilization is considered, Soybean Casein Digest is used.
gest) seeded on the medium, 1 at 32-35 ° C.
After incubation for 4 days, there must be no bacterial growth. USPXXIII <1211> “Steriz
ation and Sterility Assur
ance of Compendial Artic
Standard procedures and materials should be selected according to "les".

In a preferred embodiment, stable, sterile,
Then, an α-cyanoacrylate composition that is not substantially polymerized is provided in a glass ampoule. To package and sterilize the α-cyanoacrylate adhesive composition in a glass ampoule, use sulfur dioxide as a gas phase anionic stabilizer, and use sulfuric acid as a liquid phase anionic stabilizer. After placing in an ampoule, sealing the ampoule and before sterilizing, for a predetermined time, for example,
It is particularly preferable to leave for one day or more. This method has the consequence of reducing unwanted polymerization of the composition during and / or immediately after the sterilization step. The stable and sterile adhesive composition obtained in this way has a lower polydispersity and a lower monomer content for the undesired polymerization products than those obtained by the currently used packaging and sterilization methods. High percentage. Compositions treated in this manner have substantially no conversion of monomer to macromolecule during sterilization. Sterilization of the glass ampule containing the monomer can be performed using various sterilization methods including dry heat sterilization.

According to the embodiment of the present invention, the stability of the adhesive composition, and thus the shelf life, can be further improved. In addition, careful packing (ie, dispensing into containers) and sterilization procedures can further extend the shelf life. Contrary to the preferred embodiment described above, to minimize the time required for composition preparation and sterilization, the time to package the composition, especially in glass, and during and immediately after sterilization. A predetermined time interval from the time of disinfection, which results in the reduction of undesirable macromolecular products. In this step, the interval between the time for installing the liquid adhesive composition containing the monomer to be polymerized in the glass container and the time for disinfecting it is optimized. In conjunction with the novel compositions disclosed herein, this method minimizes or eliminates undesirable levels of polymerization of the monomers. Accordingly, a stable and sterile adhesive composition is provided.

Accordingly, the present invention includes a method of packaging and a method of sterilizing a monomer-containing composition for industrial or medical use. In an embodiment, the method depends on: A) separating the monomer-containing adhesive composition into a suitable container; B) depending on the monomer-containing adhesive composition and the materials used to manufacture the container. With
Standing for a predetermined time selected to enhance the stability of the composition during sterilization; C) sterilizing the composition.

The separation step (step A) of the present invention can be performed using techniques known to those skilled in the art, including but not limited to separation under an oxygen-containing atmosphere such as vacuum or air. .

The present invention further includes sealing the container. Preferably, the container is sealed between step A and step B (after separation and before standing) or after step C (after sterilization). However, sealing of the container after step B (after standing for a predetermined time) is also possible in the present invention. If the container is sealed after step C, care must be taken not to impair the sterility of the composition. Most preferably, the container is sealed between step A and step B.

The interval between the time for separating the monomer composition and the time for sterilizing the composition is such that a composition whose viscosity has increased immediately after sterilization within a range of 15 to 20% or less of the viscosity before sterilization is obtained. It is preferable to adjust as follows. However, an increase in viscosity up to 200% of the viscosity before sterilization is acceptable. Further, the sterilized composition preferably has a viscosity of 50% or less of the composition before sterilization. Most preferably, the viscosity of the composition does not change (ie, less than 20%) before and after the sterilization treatment. In order for the monomer adhesive composition to have high practicability in applications to which the monomer adhesive composition is applied, the viscosity increase of the composition after sterilization must be 200% or less of the viscosity before sterilization. In general, an increase in viscosity during sterilization can be determined as premature aging of the monomer-containing composition. This degrades its useful shelf life, especially if it is not stored at low temperatures. In addition, changes in viscosity are also indicators of changes in reactivity of the monomer-containing composition, which are generally undesirable.

The predetermined time interval depends on the compatibility of the monomer, the packing material, and the stabilizer used. If a glass container is used, the predetermined time interval is preferably at least one day (24 hours), typically about 2 days. The upper limit of the predetermined time is determined only from the viewpoint of practical use and convenience of the user.

Without limitation to any description,
The predetermined time interval between the time for separating the composition and the time for sterilizing the composition is a non-stable material in which a stabilizer, particularly a liquid phase anionic stabilizer, is present on the surface of the packaging material. And provide sufficient time for removal. For example,
Sealing the glass container produces a clean glass. Leaving after sealing provides sufficient time for the anionic stabilizer to react with the fresh glass and remove any alkali material newly exposed to the composition.

The sterilization step (step C) of the present invention is performed by a method known to those skilled in the art. Although not particularly limited, it is preferable to perform the method by a method including a method using physical and irradiation means. Although any method may be used, it must be compatible with the composition to be sterilized. Although not particularly limited, heat sterilization can be exemplified as a physical method. The method using the irradiation means is not particularly limited, and examples thereof include gamma ray irradiation, electron beam irradiation, and microwave irradiation. A method using heat sterilization is preferred. Most preferred is dry heat sterilization.

In an embodiment, the present invention provides a method for packaging and sterilizing a monomer-containing composition. Here, the composition also includes an adhesive for medical use. In a preferred embodiment, polymerization of the monomer liquid phase adhesive composition is substantially not initiated. Such polymerization affects the utility of the monomers caused by the sterilization process. The aseptic liquid phase adhesive composition exhibits good shelf life and excellent stability.

The monomer composition in the examples is preferably a monomer adhesive composition (including a prepolymer). In an embodiment, the monomer is a 1,1-disubstituted ethylene monomer, for example, α-cyanoacrylate. The preferred monomer composition of the present invention and the polymer obtained therefrom can be effectively used as a tissue adhesive or patch for stopping bleeding or covering open wounds. Furthermore, it can be used for other absorbing and non-absorbing biochemical applications. For example, it can be used on surgical incisions or on externally dissected tissue. In addition, it delays the blood flowing out of the wound, allows for drug transport, burns, treats skin (or other superficial or other surface wounds (abrasions and raw wounds, and / or stomatitis)), hernia treatment , Meniscus treatment, living tissue repair and regrowth, etc. Other preferred monomers of the present invention, and polymers derived therefrom, can be used in bonded rubber, plastics, wood, composites, textiles, other natural and synthetic materials, and the like.

The monomers used in the present invention are polymerized immediately. For example, a polymer is formed by anionic polymerization, free radical polymerization, or polymerization using an amphoteric ion or an ion pair. Such monomers include those that form polymers, but are not required to be biodegradable. Such monomers include, for example, USP 5, by Leung et al.
328,687 can be used. All the monomers described there can be used in the present invention. The 1,1-disubstituted ethylene monomer useful in the present invention is not particularly limited, but it is preferable to use a monomer represented by the following formula (I). (I) HRC = CXY where X and Y are each a strong electron-withdrawing group,
Is H or -CH = CH _2, if both the X and Y is a cyano group, a C ₁ -C ₄ alkyl group.

Examples of monomers included in formula (I) include:
α-cyanoacrylate, vinylidene cyanide, C ₁ -C ₄ alkyl homologues of vinylidene cyanide, dialkylmethylene malonate, acylacrylonitrile, vinyl sulfinate, and vinyl sulfonate of CH ₂ ＣCX′Y ′ ( Here, X ′ is —SO ₂ R ′ or —S
O ₃ R ′, Y ′ is —CN, —COOR ′, —CO
CH ₃ , —SO ₂ R ′, or —SO ₃ R ′;
R ′ is H, or hydrocarbyl (hydrocarbyl)
yl). ).

The preferred monomer of formula (I) used in the present invention is α-cyanoacrylate. These monomers are known to those skilled in the art, and have the formula (II) of Formula 1 where R ² is hydrogen and R ³ is a hydrocarbyl or substituted hydrocarbyl group;
A group having ^4- OR ⁵ -OR ⁶ (where R ⁴ is 2
A 1,2-alkylene group having from 4 to 4 carbon atoms,
R ⁵ is an alkylene group having 2 to 4 carbon atoms,
R ⁶ is an alkyl group having 1 to 6 carbon atoms. ) Or a group having the formula [Chemical Formula 2] (wherein R ⁷
Is a formula of the formula [3] (where n is 1 to 10, preferably 1)
5 to 5 carbon atoms, R ⁸ is an organic component. )have.

[0061]

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Examples of suitable hydrocarbyl and substituted hydrocarbyl groups include linear or branched 1-16
An alkyl group having 1 to 16 carbon atoms of an acyloxy group, an alkyl group having 1 to 16 carbon atoms, a haloalkyl group, an alkoxy group, a halogen atom, a cyano group,
Or a haloalkyl group; a linear or branched alkenyl group having 2 to 16 carbon atoms; a linear or branched alkynyl group having 2 to 12 carbon atoms; a cycloalkyl group; an aralkyl group; It can be enumerated including an aryl group.

The organic component R ⁸ may be substituted or unsubstituted and may be linear, branched or cyclic, saturated, unsaturated,
Or it may be aromatic. Examples of such organic components include alkyl components of 1 to 8 carbon atoms, alkenyl components of 2 to 8 carbon atoms, alkynyl components of 2 to 8 carbon atoms, and cyclic aliphatics of 3 to 12 carbon atoms. Group components, aryl components such as phenyl and substituted phenyl, and aralkyl components such as benzyl, methylbenzyl and phenylethyl can be included and listed. Other organic components include halogen components (e.g., chloro-, fluoro-, and bromo-substituted hydrocarbons), and substituted hydrocarbon components such as oxy-substituted hydrocarbon components (e.g., alkoxy-substituted hydrocarbons). Preferred organic groups are the alkyl, alkenyl, and anikinyl moieties having 1 to about 8 carbon atoms, and halogen-substituted derivatives thereof. Particularly preferred are alkyl components of 4 to 6 carbon atoms.

In the cyanoacrylate monomer of formula (II), R ³ is preferably an alkyl group having 1 to 10 carbon atoms, or a formula —AOR ^9, wherein A is 2 to 8 carbon atoms. R ⁹ is a straight-chain or branched-chain alkyl component having 1 to 8 carbon atoms.

Examples of the group represented by the formula -AOR ⁹ include:
1-methoxy-2-propyl, 2-butoxyethyl, isopropoxyethyl, 2-methoxyethyl, and 2-methoxyethyl
It can be listed including ethoxyethyl.

The α-cyanoacrylate of formula (II) can be prepared by methods known in the art. U. S.
Japanese Patent Nos. 2721858 and 3254111 disclose α
-Discloses the preparation of cyanoacrylates, which is incorporated by reference in its entirety. For example, α-cyanoacrylate can be prepared by reacting an alkyl cyanoacetate with formaldehyde in a non-aqueous organic solvent in the presence of a basic catalyst, followed by thermal decomposition of an anhydrous intermediate polymer in the presence of a polymerization inhibitor. . Alpha-cyanoacrylate monomers prepared with low water content and essentially free of impurities are suitable for biomedical applications.

Formula (II) (R ³ is a group represented by the formula R ⁴ —O—R ⁵ —O
A group having a -R ^6. Α-cyanoacrylate of U.S.A. S. It can be prepared according to the method disclosed in Japanese Patent No. 4364876, Kimura et al. The whole is taken in by this reference. In this Kimura et al. Method, α-cyanoacrylate is formed by esterifying cyanoacetic acid with an alcohol to form a cyanoacetate, or transesterifying an alkyl cyanoacetate with an alcohol; and converting cyanoacetate with formaldehyde or para-formaldehyde. In the presence of a catalyst in a molar ratio of 0.5 to 1.5: 1, preferably 0.8 to 1.2: 1 to obtain a condensate;
Prepared by depolymerizing the condensation reaction mixture immediately or after removing the condensation catalyst to obtain the crude cyanoacrylate; and distilling the crude cyanoacrylate to obtain high purity cyanoacrylate.

The α-cyanoacrylate of the formula (II) (where R ³ is a group having the group of the formula [4]) is described in US Pat. S. Patent No. 3995941, Kronentha
It can be prepared according to the procedures described elsewhere and is incorporated by reference in its entirety. In the method of Kronenthal et al., Such α-cyanoacrylate monomers are converted to α-cyanoacrylate monomers.
The alkyl ester of cyanoacrylic acid is reacted with a cyclic 1,3-diene to form a Diels-Alder adduct, which is then alkali-hydrolyzed and acidified to form the corresponding α-cyanoacrylic adduct. It is prepared by The α-cyanoacrylic acid adduct is preferably esterified with an alkyl bromoacetate to form the corresponding carbalkoxymethyl α-cyanoacrylate adduct. Alternatively, the α-cyanoacrylic acid adduct may be reacted with thionyl chloride to convert to an α-cyanoacryl halide adduct. The α-cyanoacryl halide adduct is then reacted with an alkyl hydroxyacetate or a methyl-substituted alkyl hydroxyacetate to give the corresponding carbalkoxymethyl α-cyanoacrylate adduct or carbalkoxyalkyl α-cyanoacrylate adduct. Get each. The cyclic 1,3-diene blocking group is finally removed and the carbalkoxymethyl α-cyanoacrylate adduct or carbalkoxyalkyl α-cyanoacrylate adduct is slightly depleted in the presence of maleic anhydride. Is converted to the corresponding carbalkoxyalkyl α-cyanoacrylate by heating the adduct.

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Examples of the monomer of the formula (II) include cyanopentadienoic acid ester and the compound of the formula (III)
(Wherein, Z is -CH = CH _2, R ³ are as described above.) Can be enumerated include α- cyanoacrylate. A monomer of formula (III) wherein R ³ is 1
Alkyl groups of from 10 to 10 carbon atoms. That is, 2-
Cyanopenta-2,4-dienoate is a suitable 2
-Can be prepared by reacting cyanoacetate with acrolein in the presence of a catalyst such as zinc chloride. 2
This process for the preparation of -cyanopenta-2,4-dienoic acid esters is described, for example, in US Pat. S. No. 3,554,990, which is incorporated by reference in its entirety.

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Preferred α-cyanoacrylates for use in the present invention are alkyl α-cyanoacrylates, including octyl cyanoacrylate such as 2-octyl cyanoacrylate; dodecyl cyanoacrylate; ethylhexyl cyanoacrylate; cyanoacrylic Methoxyethyl acid;
2-ethoxyethyl cyanoacrylate; butyl cyanoacrylate such as n-butyl cyanoacrylate; ethyl cyanoacrylate; methyl cyanoacrylate; 3-methoxybutyl cyanoacrylate; 2-butoxyethyl cyanoacrylate; cyanoacryl 2-cisisopropoxyethyl acid; and 1-methoxy-2-propyl cyanoacrylate. More preferred monomers are ethyl α-cyanoacrylate, n-butyl α-cyanoacrylate and α-cyanoacrylate.
-2-octyl cyanoacrylate. The monomers used for the medical purposes of the present invention are required to be very pure and to be substantially free of impurities (eg, to the extent of surgical applications). Monomers used for industrial purposes need not be so pure.

The composition may optionally contain additives such as plasticizers, thixotropic agents, natural rubber or synthetic rubber. Such additives are well-known to those skilled in the art. In general, when such additives are included in the adhesive composition, the composition becomes unstable, for example, having a reduced shelf life or adverse effect on cure rate. However, the compositions of the present invention do not show the level of adverse effects seen in the prior art when including these known additives. Thus, the present invention is an improvement over currently available compositions.

The composition can optionally include at least one plasticizer that imparts flexibility to the polymer formed from the monomers. The plasticizer should preferably contain little or no moisture and should not significantly affect the stability or polymerization of the monomer. Such plasticizers are useful in polymerized compositions for closing and covering wounds, cuts, abrasions, sores, or for other applications where the flexibility of the adhesive is desired.

Examples of suitable plasticizers include acetyltributyl citrate, dimethyl sebacate, triethyl phosphate, tri (2-ethylhexyl) phosphate, tri (p-cresyl) phosphate, glyceryl triacetate and glyceryl tributyrate. , Diethyl sebacate, dioctyl adipate, isopropyl myristate, butyl stearate, lauric acid, trioctyl trimellitate
ate), dioctyl glutarate, and mixtures thereof. Preferred plasticizers are tributyl citrate and acetyl tributyl citrate.
Specifically, suitable plasticizers are polyethylene glycol (PEG) esters and capped (capp)
ed) Polymerizable plasticizers such as PEG esters or ethers, glutaric polyesters and adipic polyesters.

No plasticizer is added by adding the plasticizer in an amount of up to 60% by weight, preferably up to 50% by weight, more preferably up to 30% by weight and most preferably up to 10% by weight. The film strength (eg, tenacity) of the polymerized monomer over the polymerized monomer is increased.

The composition can also optionally include at least one thixotropic agent. Suitable thixotropic agents are known to those skilled in the art, and may include, but are not limited to, silica gel and the like treated with silyl isocyanate. Examples of suitable thixotropic agents include, for example, U.S. Pat. S. Patent No. 4720
No. 513, which is incorporated by reference in its entirety.

The composition may also include at least one natural or synthetic rubber to provide impact resistance. This is preferred especially when the composition of the present invention is used industrially. Suitable rubbers are known to those skilled in the art. Such rubbers can be listed including diene, styrene, acrylonitrile, and mixtures thereof,
It is not limited to this. Examples of suitable rubbers are described, for example, in US Pat.
S. Nos. 4,313,865 and 4,560,723, which are incorporated by reference in their entirety.

The composition of the present invention comprises at least one radical stabilizer. Examples of suitable radical stabilizers include hydroquinone, hydroquinone monomethyl ether, catechol, pyrogallol, benzoquinone,
-Hydroxybenzoquinone, p-methoxyphenol,
t-butylcatechol, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT),
T-butylhydroquinone, and mixtures thereof, may be mentioned. Specifically, the amount of stabilizer such as BHA is about 1000-5000 ppm.

The compositions used in the medical applications of the present invention are also biocompatible, effective in reducing the concentration of active formaldehyde produced during biodegradation of the polymer in vivo. At least one drug (hereinafter referred to as "formaldehyde concentration reducing agent") can be included. Preferably, this component is a formaldehyde scavenger compound. Examples of formaldehyde scavenger compounds useful in the present invention include sulfites; bisulphite (bisul).
a mixture of sulfite and bisulfite; amonium sulfite; amine; amide; imide; nitrile; carbamate; alcohol; mercaptan; protein; a mixture of amine, amide and protein; a cyclic ketone and b-dicarbonyl group; An active methylene compound, such as a compound having a carbonyl group; and a heterocyclic compound containing an NH group without a carbonyl group and formed from a nitrogen atom or a carbon atom (when this ring is unsaturated or bonded to a phenyl group, Unsaturated or saturated, and the NH group is bonded to a carbon atom or a nitrogen atom, and this atom is directly bonded to another carbon atom or a nitrogen atom by a double bond.)

The bisulfites and sulfites useful as formaldehyde scavenger compounds in the present invention are lithium salts,
Sodium salts, alkali metal salts such as potassium salts, ammonium salts such as sodium bisulfite, potassium bisulfite, lithium bisulfite, ammonium bisulfite,
Sodium sulfite, potassium sulfite, lithium sulfite,
Ammonium sulfite and the like.

Examples of amines useful in the present invention include, for example, aliphatic and aromatic amines such as aniline, benzidine, aminopyrimidine, toluene-diamine, triethylenediamine, diphenylamine, diaminodiphenylamine, hydrazine, and hydrazide. Can be enumerated.

[0081] Suitable proteins include collagen, gelatin, casein, soy protein, vegetable protein, and keratin. A preferred protein for use in the present invention is casein.

Preferred amides for use in the present invention include urea, cyanamide, acrylamide, benzamide, and acetamide. The preferred amide is urea.

Preferred alcohols are phenol, 1,4-
Includes butanediol, d-sorbitol, and polyvinyl alcohol.

Examples of suitable compounds having a b-dicarbonyl group include malonic acid, acetylacetone, ethylacetone, acetate, malonamide, diethyl malonate, or another malonic ester.

[0085] Preferred cyclic ketones for use in the present invention include cyclohexanone or cyclopentanone.

Examples of suitable heterocyclic compounds for use as the formaldehyde scavenger of the present invention include, for example,
U. S. No. 4,127,382, disclosed in Perry, which is incorporated by reference in its entirety. Such heterocyclic compounds include, for example, benzimidazole, 5-methylbenzimidazole, 2-methylbenzimidazole, indole, pyrrole, 1,2,4-triazole, indoline, benzotriazole, indoline and the like.

A preferred formaldehyde scavenger for use in the present invention is sodium bisulfite.

In the practice of the present invention, the formaldehyde concentration reducing agent is added to the cyanoacrylate in an effective amount. "Effective amount" refers to an amount sufficient to reduce the amount of formaldehyde formed during subsequent biodegradation of the polymerizable cyanoacrylate in vivo. This amount depends on the type of active formaldehyde concentration-lowering agent and can be easily determined without difficulty by those skilled in the art.

Although the formaldehyde concentration reducing agent can be used in the present invention, the form may be a free form or a form encapsulated in microcapsules. In the microencapsulated form, the formaldehyde concentration-lowering agent is released from the microcapsules continuously throughout the in vivo biodegradation of the cyanoacrylate polymer.

For purposes of the present invention, the formaldehyde concentration reducing agent is preferably in a microencapsulated form.
The reason is that, according to this example, the polymerization of the cyanoacrylate monomer is inhibited or substantially reduced by the formaldehyde concentration-lowering agent, so that the storage life and the handling of the monomer composition during use are facilitated.

Microencapsulation of the formaldehyde scavenger can be accomplished by a number of known microencapsulation techniques. For example, microencapsulation involves dissolving the coating polymer in a volatile solvent (eg, methylene chloride) at about 6% by weight of the polymer concentration; adding the particulate formaldehyde scavenger compound to the coating polymer / solvent solution with stirring. Bringing the scavenger concentration to 18% by weight;
Adding the surfactant-containing mineral oil solution slowly into the polymer solution under rapid stirring and evaporating the volatile solvent under stirring; removing the stirrer; separating the solids from the mineral oil; washing and drying the microparticles It is performed by The size of the microparticles is from about 0.001 to about 1000 microns.

The coating polymer for microencapsulating the formaldehyde concentration-lowering agent should preferably be the same as the cyanoacrylate polymer formed by the monomers but at a faster rate in vivo bioerosion. It must be an intrinsic water content. Such bioerosion can occur, for example, when the capsule material is physically or chemically degraded by the capsule material passing from a solid to a solute in the presence of body fluids, or by biodegradation of the capsule material by drugs present in the body. It can occur as a result of chemical breakdown.

Examples of coating materials that can be used to microencapsulate the formaldehyde concentration reducing agent include polyglycolic acid, polylactic acid, poly1,4-dioxa-2-one, polyoxalate, polycarbonate, polycarbonate, and the like. Polyesters such as copolymers of glycolic acid and polylactic acid, polycaprolactone, poly-b-hydroxybutyrate, copolymers of epsilon-caprolactone and delta-valerolactone, copolymers of epsilon-caprolactone and DL-dilactide, and polyester hydrogels; polyvinylpyrrolidone Polyamide; gelatin; albumin; protein; collagen;
Poly (anhydride); Poly (anhydride); Poly (alkyl-2-cyanoacrylate); Poly (dihydropyran); Poly (acetal); Poly (phosphazene); Poly (urethane); Poly (dioxinone); ;
And starch.

Examples of surfactants that can be added to mineral oil
Is Triton X-100^TM(Rohm and Haa
s), Tween20^TM(ICI America) and Tw
een80 ^TM(ICI America) and marketed
Can be enumerated including those that have been described.

The compositions of the present invention can optionally include at least one thickening agent. Suitable thickeners include, for example, polycyanoacrylate, polylactic acid, poly-1,4-dioxa-2-one, polyoxalate, polyglycolic acid, copolymers of lactic acid and glycolic acid, polycaprolactone, lactic acid and Listed are copolymers of caprolactone, poly-3-hydroxybutyric acid, polyorthoesters, polyalkyl acrylates, copolymers of alkyl acrylates and vinyl acetate, polyalkyl methacrylates, and copolymers of alkyl methacrylate and butadiene. Examples of alkyl methacrylate and alkyl acrylate include poly (2-ethylhexyl methacrylate) and poly (2-ethylhexyl acrylate), and poly (butyl methacrylate) and poly (butyl acrylate), and poly (butyl acrylate). Various copolymers of acrylate monomers and methacrylate monomers, such as butyl methacrylate-co-methyl acrylate, can be listed.

In order to improve the cohesive strength of the adhesive formed from the composition of the present invention, a bifunctional monomer crosslinking agent can be added to the monomer composition of the present invention. Such crosslinking agents are known. U. S. Patent No. 3940362, O
Verhults discloses such cross-linking agents, which are incorporated by reference in their entirety. Examples of suitable crosslinking agents include alkyl bis (2-cyanoacrylate), triallyl isocyanurate, alkylene diacrylate, alkylene dimethacrylate, trimethylolpropane triacrylate, and alkyl bis (2
-Cyanoacrylate). A catalytic amount of an amine-activated free radical initiator or rate modifier is added to initiate polymerization or to regulate the rate of polymerization of the cyanoacrylate monomer / crosslinker blend.

The compositions of the present invention may further include fiber reinforcements and coloring agents such as dyes, pigments, and pigment dyes. Examples of suitable fiber reinforcements include and include PGA microfibrils, collagen microfibrils, cellulose microfibrils, and olefin microfibrils. Examples of suitable coloring agents include 1-hydroxy-4- [4-methylphenylamino] -9,10 anthracenedione (D + C Purple No.
2); 6-hydroxy-5-[(4-sulfophenyl) oxo] -2-naphthalene-sulfonic acid disodium salt (FD + C yellow No. 6); 9- (o-carboxyphenyl) -6-hydroxy- 2,4,5,7-tetraiodo-3H-xanthen-3-one, disodium salt, monohydrate (FD + C red No. 3); 2- (1,3-
Dihydro-3-oxo-5-sulfo-2H-indole-2-iridine) -2,3-dihydro-3-oxo-1
H-indole-5-sulfonic acid disodium salt (FD
+ C blue No. 2); and [phthalocyaninato (2
-)] Can be listed including copper.

Other compositions and additives contemplated by the present invention are described in US Pat. S. Patent Nos. 5,624,669 and 55,828
No. 34, No. 5,575,997, No. 5,514,371, No. 5,514,372 and No. 5,259,835. S. It is illustrated in application Ser. No. 08/714288, which is incorporated by reference in its entirety.

[0099]

【Example】

Example 1 Encapsulation and sterilization of a prior art 2-octylcyanoacrylate composition in a glass container. Table 1 shows the effect of waiting for a predetermined time before sterilizing the 2-octylcyanoacrylate adhesive composition containing sulfur dioxide as the only anionic stabilizer. The data in Table 1 was obtained as follows. 2-octylcyanoacrylate, 20 to 40 ppm
Of sulfur dioxide, 1500 ppm of hydroxyquinoline, and
A composition is prepared containing 145 ppm paramethoxyphenol and 150 ppm acetic acid. Half a milliliter (0.5 ml) of the composition is dispersed in a glass bottle (ampoule). The open end of the bottle is heated and sealed until the glass melts. Sealed bottles can be kept for a certain period of time (for example, 2 hours or 120 hours)
(1 to 25 ° C). This temperature is not critical, but during this time the bottle should not be overheated. Thereafter, the sealed bottle is dried and sterilized at 160 ° C. for 1 hour. The obtained germicidal composition is cooled to room temperature.

The sterilized 2-octylcyanoacrylate composition is discharged from the bottle and tested for viscosity according to the method described above.

Fourteen different preparations of the same 2-octylcyanoacrylate composition were prepared and tested in this manner.
A sample of each preparation was left for 2 or 120 hours between dispersion and sterilization. Table 1 shows the centipoise viscosities of the 14 samples before and after sterilization.

It can be seen from Table 1 that the 2-octylcyanoacrylate composition stabilized with sulfur dioxide as the only anionic stabilizer was not added to the unsterilized composition even after 120 hours between dispersion and sterilization. On the other hand, it can be seen that it has a viscosity of at least 122%. Average is about unsterilized composition
170%.

[0103]

[Table 1]

Example 2 Effect on viscosity of waiting a predetermined time of the composition of the present invention. 17.5 ppm sulfuric acid (liquid phase anionic stabilizer), 15
ppm sulfur dioxide (gas phase anionic stabilizer), 1500 ppm
A 2-octylcyanoacrylate composition containing hydroxyquinoline and 145 ppm of paramethoxyphenol (free radical stabilizer) and 150 ppm of acetic acid was dispersed in a glass ampule, and the ampule was sealed. The product was left at room temperature for the indicated time and then sterilized by drying and heating. The viscosity was determined according to the method described above.

The experimental results are shown in Table 2. When the composition of the present invention was sterilized after waiting for a predetermined time, the viscosity was reduced as compared with sterilizing the composition immediately after dispersing and sealing the glass bottle.

Furthermore, in comparison with the results obtained in Table 1, the compositions according to the invention show a viscosity of at most only 113%, based on the unsterilized composition, after waiting for only 46 hours and sterilizing them. . On average, these compositions showed, after sterilization, a viscosity of only 107% before sterilization. Thus, the compositions of the present invention are more stable than prior art compositions.

[0107]

[Table 2]

Example 3 Stabilization of a sterilized cyanoacrylate composition. The indicated amounts of sulfur dioxide (gas phase anionic stabilizer) and sulfuric acid
A 2-octylcyanoacrylate composition containing (liquid-phase strong acid anion stabilizer) was prepared. It contains 1500 ppm of hydroxyquinoline, and 145 ppm of paramethoxyphenol (as a free radical stabilizer) and 150 ppm of acetic acid (as a second anionic activator). This was dispersed in a glass ampule, the ampule was then sealed, and left at room temperature for 2 days. Thereafter, the packaged composition was dried and heat sterilized at 160 ° C. for 1 hour. The samples were then cooled and the viscosity of the composition from one bottle of each sample was
The measurement was performed in the same manner as in 1 and 2.

Another bottle of each composition was heated to 80 ° C. for 12 days. This treatment can easily simulate the effect in a composition stored for 2 years at ambient temperature.

Table 3 shows the results. The results show that the 2-cyanoacrylate composition containing at least 5 ppm sulfuric acid and sulfur dioxide as a gas phase anionic stabilizer has little or no increase in viscosity during or immediately after dry heat sterilization. Is shown. Also, these compositions exhibit significant stability over extended storage periods.

[0111]

[Table 3]

The present invention has been described with reference to the preferred embodiments. The present invention is not limited to the specific examples described, but can be easily modified by those skilled in the art to other examples within the present invention.

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[Procedure amendment]

[Submission date] February 10, 1999 (1999.2.1
0)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claims

[Correction method] Change

[Correction contents]

[Claims]

35. A combination of a polymerizable 1,1-disubstituted ethylene monomer, at least one gas phase anionic stabilizer, at least one liquid phase anionic stabilizer, and at least one radical stabilizer. A method for producing an adhesive composition by heating. ────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission Date] October 6, 1999 (1999.10.
6)

[Procedure amendment 1]

[Document name to be amended] Statement

[Correction target item name] Claim 1

[Correction method] Change

[Correction contents]

[Procedure amendment 2]

[Document name to be amended] Statement

[Correction target item name] Claim 2

[Correction method] Change

[Correction contents]

[Procedure amendment 3]

[Document name to be amended] Statement

[Correction target item name] Claim 3

[Correction method] Change

[Correction contents]

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] Claim 4

[Correction method] Change

[Correction contents]

[Procedure amendment 5]

[Document name to be amended] Statement

[Correction target item name] Claim 11

[Correction method] Change

[Correction contents]

[Procedure amendment 6]

[Document name to be amended] Statement

[Correction target item name] Claim 16

[Correction method] Change

[Correction contents]

[Procedure amendment 7]

[Document name to be amended] Statement

[Correction target item name] Claim 17

[Correction method] Change

[Correction contents]

[Procedure amendment 8]

[Document name to be amended] Statement

[Correction target item name] Claim 18

[Correction method] Change

[Correction contents]

[Procedure amendment 9]

[Document name to be amended] Statement

[Correction target item name] Claim 20

[Correction method] Change

[Correction contents]

20. A container for holding at least one polymerizable 1,1-disubstituted monomer adhesive composition and for treating wounds.
Or have pharmaceutically effect has a function, the kit comprising a container holding at least one drug.

[Procedure amendment 10]

[Document name to be amended] Statement

[Correction target item name] Claim 21

[Correction method] Change

[Correction contents]

21. The kit according to claim 20 , wherein the adhesive composition is the adhesive composition according to any one of claims 1 to 18.

[Procedure amendment 11]

[Document name to be amended] Statement

[Correction target item name] Claim 22

[Correction method] Change

[Correction contents]

22. A method for sterilizing an adhesive composition according to any one of claims 1 to 18, the composition was dispersed in the container, the container is sealed, the adhesive composition and A sterilization method, wherein the container is sterilized.

[Procedure amendment 12]

[Document name to be amended] Statement

[Correction target item name] Claim 23

[Correction method] Change

[Correction contents]

23. dry heat, gamma radiation, according to claim 2, sterilized by electron beam radiation or microwave radiation
2. The sterilization method described in 2 .

[Procedure amendment 13]

[Document name to be amended] Statement

[Correction target item name] Claim 24

[Correction method] Change

[Correction contents]

24. The method of claim 2, sterilized by the dry heat
23. The sterilization method according to 2 or 23 .

[Procedure amendment 14]

[Document name to be amended] Statement

[Correction target item name] Claim 25

[Correction method] Change

[Correction contents]

25. The method of claim 2 , wherein the sterilization is effected by gamma radiation.
A sterilization method according to any one of 2 to 24 .

[Procedure amendment 15]

[Document name to be amended] Statement

[Correction target item name] Claim 26

[Correction method] Change

[Correction contents]

26. sterilization method as claimed in any one of claims 22 to 25 total volume of the composition dispersed in the vessel is less than 1 milliliter.

[Procedure amendment 16]

[Document name to be amended] Statement

[Correction target item name] Claim 27

[Correction method] Change

[Correction contents]

27. A method according to claim 27 , wherein said dispersing composition waits for a predetermined period of time sufficient to prevent or eliminate polymerization of said monomer during sterilization before sterilization or immediately after sterilization. A sterilization method according to any one of 22 to 26 .

[Procedure amendment 17]

[Document name to be amended] Statement

[Correction target item name] Claim 28

[Correction method] Change

[Correction contents]

28. The container, wherein the container is made of glass, the at least one gas phase anionic stabilizer in a sterilized composition is sulfur dioxide, and the at least one liquid phase anionic stabilizer is sulfuric acid. The sterilization method according to any one of claims 22 to 27 , comprising:

[Procedure amendment 18]

[Document name to be amended] Statement

[Correction target item name] Claim 29

[Correction method] Change

[Correction contents]

29. wherein said predetermined time is sterilization method as claimed in claim 28, characterized in that at least 24 hours.

[Procedure amendment 19]

[Document name to be amended] Statement

[Correction target item name] Claim 30

[Correction method] Change

[Correction contents]

30. The method of any of claims 22-29 , wherein said sterilized composition has a viscosity of less than 300% of its viscosity before sterilization.

[Procedure amendment 20]

[Document name to be amended] Statement

[Correction target item name] Claim 31

[Correction method] Change

[Correction contents]

31. A composition described above sterilization, sterilization method as claimed in any one of claims 22-29, characterized in that it has a viscosity of less than 300% of its viscosity before sterilization.

[Procedure amendment 21]

[Document name to be amended] Statement

[Correction target item name] Claim 32

[Correction method] Change

[Correction contents]

32. A fungicidal adhesive composition was prepared by sterilization method as claimed in any one of claims 22-31.

[Procedure amendment 22]

[Document name to be amended] Statement

[Correction target item name] Claim 33

[Correction method] Change

[Correction contents]

33. A combination of a polymerizable 1,1-disubstituted ethylene monomer, at least one gas phase anionic stabilizer, at least one liquid phase anionic stabilizer, and at least one radical stabilizer. A method for producing an adhesive composition by heating.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification FI FI Theme Court ゛ (Reference) C09J 4/04 C09J 11/02 11/02 A61L 15/01 (72) Inventor Andre Rivera United States 27616 Raleigh, North Carolina Whisperwood Drive 4420 (72) Inventor Gabriella Ruda United States of America North Carolina 27613 Raleigh River Run 6912-12

Claims (35)

[Claims] 1. A polymerizable 1,1-disubstituted ethylene monomer in a liquid phase and a gas phase, at least one gas phase anionic stabilizer and at least one liquid phase anionic stabilizer, The at least one liquid phase anionic stabilizer is a very strong acid, or at least one liquid phase anionic stabilizer is a strong acid, and the at least one gas phase anionic stabilizer is trifluoride. An adhesive composition comprising at least one compound selected from the group consisting of boron and hydrogen fluoride. 2. The adhesive composition according to claim 1, wherein said at least one liquid phase anionic stabilizer is a very strong acid. 3. The at least one liquid phase anionic stabilizer is a strong acid, and the at least one gas phase anionic stabilizer is at least one selected from the group consisting of boron trifluoride and hydrogen fluoride. 2. A compound comprising one compound.
The adhesive composition according to item 1. 4. The adhesive composition according to claim 1, further comprising at least one radical stabilizer. 5. The method according to claim 1, wherein the monomer is at least one compound selected from the group consisting of n-butyl cyanoacrylate, 2-octyl cyanoacrylate, ethyl cyanoacrylate, methyl cyanoacrylate, ethoxymethyl cyanoacrylate and methoxyethyl cyanoacrylate. The adhesive composition according to any one of claims 1 to 4, wherein: 6. The adhesive according to claim 2, wherein said at least one gas-phase anionic stabilizer comprises at least one compound selected from the group consisting of sulfur dioxide, boron trifluoride and hydrogen fluoride. Composition. 7. The adhesive composition according to claim 6, wherein said at least one gas-phase anionic stabilizer comprises sulfur dioxide. 8. The adhesive composition according to claim 2, wherein said at least one gas-phase anionic stabilizer comprises boron trifluoride. 9. The method according to claim 2, wherein said at least one liquid phase anionic stabilizer comprises at least one compound selected from the group consisting of sulfuric acid, perchloric acid, fluorosulfonic acid and chlorosulfonic acid. Adhesive composition. 10. The adhesive composition according to claim 7, wherein said at least one liquid phase anionic stabilizer comprises sulfuric acid. 11. The adhesive composition according to claim 10, further comprising at least one compound selected from the group consisting of boron trifluoride and hydrogen fluoride. 12. The adhesive composition according to claim 2, wherein said at least one liquid phase anionic stabilizer comprises an organic sulfonic acid. 13. The adhesive composition according to claim 4, wherein said at least one radical stabilizer is a compound selected from the group consisting of butylated hydroxyanisole and butylated hydroxytoluene. 14. The adhesive composition according to claim 1, further comprising boron trifluoride. 15. The adhesive composition according to claim 1, wherein the composition is sterilized. 16. The adhesive composition according to claim 1, wherein said composition further comprises a second anionic agent. 17. The adhesive according to claim 16, wherein the second anionic agent comprises at least one compound selected from the group consisting of phosphoric acid, acetic acid, benzoic acid, chloroacetic acid, and cyanoacetic acid. Composition. 18. The adhesive composition according to claim 1, further comprising at least one drug. 19. A polymerized composition obtained by polymerizing the adhesive composition according to any one of claims 1 to 13. 20. A method for producing a composition for treating a wound by applying the adhesive composition according to claim 1 to the wound and polymerizing the wound. 21. A composition for treating a wound by applying at least one agent to the surface of the wound and applying the composition on the at least one agent to form an adhesive composition. Manufacturing method. 22. A kit comprising a container holding at least one polymerizable 1,1-disubstituted monomer adhesive composition and a container holding at least one drug. 23. The kit according to claim 22, wherein the adhesive composition is the adhesive composition according to any one of claims 1 to 13. 24. A method for sterilizing the adhesive composition according to claim 1, wherein the composition is dispersed in a container, the container is sealed, and the composition and the container are disinfected. A sterilization method for requesting sterilization. 25. Sterilization by dry heating, gamma ray radiation, electron beam radiation or microwave radiation.
4. The sterilization method described in 4. 26. The method according to claim 2, wherein said paste is sterilized by said drying and heating.
5. The sterilization method according to 5. 27. Sterilization by gamma radiation.
5. The sterilization method according to 5. 28. The sterilization method according to claim 24, wherein the total volume of the composition dispersed in the container is less than 1 milliliter. 29. A method according to claim 29, further comprising the step of waiting for a predetermined period of time sufficient to prevent or eliminate polymerization of the monomer during or before sterilization of the dispersed composition. The sterilization method described in 24. 30. The container, wherein the container is made of glass, the at least one gas phase anionic stabilizer in a sterilized composition is sulfur dioxide, and the at least one liquid phase anionic stabilizer is sulfuric acid. The sterilization method according to claim 24, comprising: 31. The sterilization method according to claim 29, wherein the predetermined time is at least 24 hours. 32. A method according to any of claims 24-31, wherein said sterilized composition has a viscosity of less than 300% of its viscosity before sterilization. 33. A method according to any of claims 24-31, wherein said sterilized composition has a viscosity of less than 300% of its viscosity before sterilization. 34. A germicidal adhesive composition produced by the germicidal method according to any one of claims 24-31. 35. A combination of a polymerizable 1,1-disubstituted ethylene monomer, at least one gas phase anionic stabilizer, at least one liquid phase anionic stabilizer, and at least one radical stabilizer. A method for producing an adhesive composition by heating.